The normal functioning of the vascular endothelial cells is of crucial importance for the body. These cells form an edge surface between the circulating blood and the elements of the vein wall performing thrombogenous activity. The role of the vascular endothelial cells in homeostasis is quite varied:
they participate in the two-way transport of substances originating from the blood and the tissues, PA1 they form a barrier for the macromolecules, PA1 these cells are the location of the synthesis and the decomposition of the mediators acting in the regulation of the interaction between the cellular elements of the vein wall and the blood (e.g. fibrinogen, collagen, proteoglycanes, PGI.sub.2, EDRF (NO), EDHF, endothelin-1, angiotensin-II), PA1 they initiate the migrational, proliferative, and thrombolytic processes contributing to histic reparation, PA1 they sustain the thromboresistance of the vein wall [Rubanyi, G., J. Cardiovasc. Pharmacol. 1993, 22 (42. Suppl., p S1-14] PA1 substitution for natural "protective" endothelial substances (e.g. stable analogues of PGI.sub.2, nitro-vasodilators, rt-PA /recombinant tissue plasminogen activator/) PA1 inhibitors or antagonists of endothelium-derived contracting factors (e.g. ACE inhibitors, angiotensin II receptor antagonists; TXA.sub.2 -receptor antagonists) PA1 cytoprotective agents (e.g. the free-radical scavengers superoxide dismutase and probucol, and free radical production inhibitor lazaroids) PA1 lipid-lowering drugs.
The impairment of the endothelium results in atherosclerosis. The impairment leading to the deterioration of the endothelium can occur at mechanic intervention, for example catheterisation, and also as the result of biochemical and immunological processes.
As the first step of the formation of atherosclerotic plaque, cells filled with lipids accumulate in the intima of the arteries (Steinberg D. et al., JAMA 264-304, 1990). These cells--especially monocytes and macrophages originating from the blood--first stick to the endothelium, and then penetrate the intima. The injury of the endothelial cells may also contribute to the adhesion, although no morphological alteration is visible in the early phase. The oxidation of the LDL particles may result in their incorporation by the monocytes located in the intima, and the monocytes thus become foam cells. These foam cells form the lipid-streaks, the earliest form of arteriosclerotic alteration.
In the later stages, bleeding, necrosis, neovascularisation, and sclerosis occur, and in the course of these, the intergrown plaque forms, which then taper the arteries (Ip. JH, Fuster et al., J. Am. Coll. Cardiol 15:1667, 1990).
Thrombosis may occur at various stages of atherosclerosis. Repeated thrombosis leads to vascular obstruction and thromboembolic illnesses, such as coronary thrombosis, the thrombosis of the brain vessels, or peripheral vascular illnesses.
In a clinical sense, "endothelial dysfunction syndrome" refers to generalised or localised vessel spasm, thrombosis, arteriosclerosis, and restenosis. Attempts to cure these illnesses have included interventional clinical techniques, bypass surgery, and medicinal treatment.
Only a few existing drugs may be suitable for the "treatment" of endothelial dysfunction. They fall into four major categories:
Although none of them were originally designed for this target, their already proven clinically beneficial effects in the case of certain illnesses may involve the protection or restoration of normal endothelial function. The rationale behind innovative therapies in this category is the restoration of normal endothelial cell lining, where these cells themselves will "do the job". Potential approaches may include stimulation of regrowth of normal endothelium, or by new emerging therapeutic modalities based on recombinant DNA technology (Science 1990; 249: 1285-8). According to the data available, no recognised drug fulfils these criteria.
These days no medicine or medicine-candidate is known to act directly on the endothelium, and thus none is suitable for treating endothelial dysfunction. Therefore, there is great therapeutical demand for a medicine which is capable of preventing, reversing, or at least slowing dowin the formation of complication symptoms, or decreasing the occurrence of the illness.